Nanosome‐Mediated Delivery Of Hdac Inhibitors and Oxygen Molecules for the Transcriptional Reactivation of Latent Hiv‐Infected Cd4⁺ T Cells

Abstract

The treatment of human immunodeficiency virus (HIV) infection is notoriously difficult due to the ability of this virus to remain latent in the host's CD4+ T cells. Histone deacetylases (HDACs) interfere with DNA transcription in HIV‐infected hosts, resulting in viral latency. Therefore, HDAC inhibitors can be used to activate viral transcription in latently infected cells, after which the virus can be eliminated through a shock‐and‐kill strategy. Here, a drug delivery system is developed to effectively deliver HDAC inhibitors to latent HIV‐infected cells. Given that the efficacy of HDAC inhibitors is reduced under hypoxic conditions, oxygen‐containing nanosomes are used as drug carriers. Oxygen‐containing nanosomes can improve the efficiency of chemotherapy by delivering essential oxygen to cells. Additionally, their phospholipid bilayer structure makes them uniquely well‐suited for drug delivery. In this study, a novel drug delivery system is developed by taking advantage of the oxygen carriers in these oxygen nanosomes, incorporating a multi‐drug strategy consisting of HDAC inhibitors and PKA activators, and introducing CXCR4 binding peptides to specifically target CD4+ T cells. Oxygen nanosomes with enhanced targeting capability through the introduction of the CXCR4 binding peptide mitigate drug toxicity and slow down drug release. The observed changes in the expression of p24, a capsid protein of HIV, indirectly confirm that the proposed drug delivery system can effectively induce transcriptional reactivation of HIV in latent HIV‐infected cells.

Noval advance of histone modification in inflammatory skin diseases and related treatment methods

“…A novel drug delivery system utilizing oxygen-containing nanosomes has been developed to efficiently transport HDAC inhibitors to dormant HIV-infected cells. Incorporating oxygen nanosomes in this study alleviates drug toxicity and regulates the rate of drug release ( 180 ). The administration of BET inhibitors also presents side effects.…”

Organelle-based immunotherapy strategies for fighting against cancer

“…Studies have shown that the inhibitors of DNA methyltransferases and histone deacetylases can elevate the expression of TH1-type chemokines to promote T cell recruitment and infiltration, as well as upregulate the antigen presenting gene. 88–90 In addition, the epigenetic antitumor drugs can reprogram cancer cells to enhance the sensitivity to PD-1/PD-L1 monoclonal antibodies. 87 Significantly, the combination of epigenetic antitumor drugs with immune checkpoint inhibitors can improve the effect of immunotherapy.…”

Bcl-2 Antagonist Obatoclax Reactivates Latent HIV-1 via the NF-κB Pathway and Induces Latent Reservoir Cell Apoptosis in Latently Infected Cells

“…In general, sustained reactivation of HIV-1 in the presence of optimal antiretroviral therapy and sufficient immune response will prevent new HIV-1 infection and eliminate HIV-1 from infected patients, albeit slowly . The “shock and kill” strategy aims to reactivate previral replication and transcription from the latent state using latency-reversing agents (LRAs), followed by the elimination of reactivated virus by cART and virus-producing cells by host immune clearance and HIV-1-specific cytolytic T lymphocytes (CTLs). − Despite extensive and in-depth research over the years on the “shock and kill” strategy for eliminating HIV-1 reservoirs, approved compounds as LRAs cannot meet this strategy. Over 160 small-molecule compounds have been developed as LRA candidates, but none have yet demonstrated effectiveness in achieving a promising functional cure .…”